The mammals of this invention heritably carry alpha-1-acid glycoprotein (AGP) genes which may be introduced by the transgenic methodology. These animal models are useful for various purposes including 1) assessment of the in vivo role of AGP in the clearance of individual drugs; 2) assessment of the influence of AGP on the pharmacological activity of individual drugs; 3) testing of hypotheses concerning the function of AGP; and 4) identification of the AGP gene cis-acting regulatory features.
AGP, a human plasma glycoprotein produced by the liver, is an acute-phase reactant--i.e., its concentration in the blood increases following inflammation.
AGP and serum albumin, the most important drug binding proteins in the plasma, present complimentary binding specificities. AGP binds mainly basic and neutral drugs whereas albumin is largely responsible for the plasma binding of acidic drugs. Such plasma binding of drugs by AGP is likely to be accompanied by important pharmacokinetic consequences (see Kremer et al., Pharmacological Review 40:1-47 (1988)). Much literature documents the in vitro binding of specific drugs by AGP whereas few studies attempt to measure the in vivo physiological and pharmacological effects of such binding. The determination of these effects is specifically addressed by the invention.